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Biomedical subjects

P D Wilson

Publications and source records attributed to P D Wilson.

At least 19 recordsLinked to original sources
PubMed1992

Abnormal extracellular matrix and excessive growth of human adult polycystic kidney disease epithelia.

Human autosomal dominant polycystic kidney disease (ADPKD) epithelia were grown in primary monolayer cultures and their properties compared with intact kidney epithelial cultures derived from individually microdissected normal human kidney proximal convoluted tubules (PCT), proximal straight tubules (PST), and cortical collecting tubules (CCT). In vivo, ADPKD cyst epithelia exhibited a thickened basement membrane, and immunofluorescence demonstrated the presence of laminin, fibronectin, type IV collagen, and heparan sulfate proteoglycan in basement membranes and type I collagen in the interstitium. ADPKD epithelia grown in culture synthesized and secreted basally a unique, extracellular matrix that took the form of proteinaceous spheroids when the cells were grown on dried, type I collagen. Incorporation of H2[S35O4] into basement membrane extracts was increased more than ten-fold in ADPKD epithelia by comparison to normal PST and CCT. In addition to incorporation into the normal tubular basement membrane 220 kD band, radioactivity was also seen at 175 kD and 150 kD in ADPKD extracts. Growth in culture of cyst-lining ADPKD epithelia was more rapid than normal tubules, and was abnormal since there was no absolute requirement for added extracellular matrix. However, when ADPKD epithelia were grown on different, exogenous matrix protein components, a profound influence on both structure and epithelial cell proliferation was seen. Growth on a complete basement membrane three-dimensional gel derived from the Engelbreth-Holm-Swarm (EHS) sarcoma led to a reduction in the numbers of spheroids and increase in amorphous filaments. Incorporation of [3H]-thymidine into ADPKD epithelia was greater than into normal PCT, PST, and CCT and was also greatly modified by the type of extracellular matrix components provided. In studies using single matrix components, the strongest proliferative response was seen when ADPKD epithelia were plated on type I collagen greater than type IV collagen greater than fibronectin greater than laminin. These findings suggest that the excessive growth of cyst-lining epithelia may be, at least in part, a result of abnormal basement membrane and extracellular matrix production by ADPKD cells.

Basement Membrane↗
PubMed1992

Age-associated decrease in vasopressin-induced renal water transport: a role for adenylate cyclase and G protein malfunction.

Aging is associated with a decline in renal concentrating ability in response to dehydration-induced arginine vasopressin (AVP) release. To examine target tissue sensitivity, cortical collecting tubules (CCT) were individually microdissected from young (3 months), middle-aged (2-3 years) and old (4-5.5 years) rabbits and subjected to in vitro perfusion analysis and tissue culture of defined epithelial monolayers. Osmotic fluid transport was compared with adenylate cyclase activity and an age-associated decline in both parameters detected in response to increasing doses of AVP. [3H]-AVP binding was unchanged in CCT epithelia of different ages, excluding receptor alterations as the underlying mechanism. Also, hydraulic conductivity measurements of isolated young and old CCT were not significantly different, excluding post-cAMP events as a major mechanism of reduced sensitivity. Effects of cholera toxin and forskolin on hydraulic conductivity and adenylate cyclase activity showed a dramatic decrease in the ability of these compounds to elicit a response in CCT epithelia from old rabbits. It was concluded that alterations in Gs proteins and the catalytic unit of adenylate cyclase-were responsible for the age-associated decline in CCT response to AVP.

Adenylyl Cyclases↗
PubMed1991

Birth weight and cardiovascular malformations: a population-based study. The Baltimore-Washington Infant Study.

Mean birth weights were evaluated in infants with D-transposition of the great arteries, tetralogy of Fallot, endocardial cushion defect, hypoplastic left heart syndrome, pulmonary stenosis, aortic stenosis, coarctation of the aorta, ventricular septal defect, and atrial septal defect in a population-based case-control study of congenital cardiovascular malformations in residents of Maryland, Washington, D.C., and northern Virginia (1981-1987). Study subjects were liveborn singletons without extracardiac anomalies. After adjustment for potentially confounding maternal, gestational, and infant factors, significant birth weight deficits were found for infants with tetralogy of Fallot, endocardial cushion defect, hypoplastic left heart syndrome, pulmonary stenosis, coarctation of the aorta, ventricular septal defect, and atrial septal defect. After adjustment, infants with these malformations (except coarctation of the aorta and atrial septal defect) were also significantly more likely than were controls to have low birth weight for gestational age. These findings strengthen previous evidence that certain cardiovascular malformations and low birth weight may be causally related.

Case-Control Studies↗
PubMed1991

A relationship between multidrug resistance and growth-state dependent cytotoxicity of the lysosomotropic detergent N-dodecylimidazole.

Multidrug resistance (MDR) in cultured cells and tumors is associated with overproduction of P-glycoprotein, a plasma membrane efflux pump normally present at very low levels. The cytotoxic action of N-dodecylimidazole (C12-Im), a lysosomotropic detergent, on cultured cells was previously shown to be strongly dependent on growth state, with rapidly growing cells being most sensitive and confluent cells most resistant. We show here that this may be due to a growth dependent increase in cellular P-glycoprotein activity. Both verapamil and nifedipine, structurally unrelated P-glycoprotein inhibitors, increased markedly the sensitivity of CHO fibroblasts to killing by C12-Im; the increase was greater in confluent than in growing cells. Also, verapamil inhibitable 3H-daunomycin efflux was more efficient from confluent than from subconfluent cells. The MDR cell line CH(R)C5 differed from all cell lines previously examined in that it did not show a growth-dependent decrease in C12-Im sensitivity, and sensitivity was not increased by verapamil or nifedipine. We suggest that a growth-dependent increase in MDR activity is a general property of cultured cells, except for those specifically overexpressing P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

The biologic effects of implant materials.

The interaction between implant materials and the surrounding biological environment continues to be an area of intense research and clinical interest. This article presents the information presented in a symposium, held during the 36th Annual Meeting of the Orthopaedic Research Society, in which several important issues concerning the biologic effects of implant materials were discussed. These issues included the mechanisms by which implant materials are released to the surrounding tissues and the ways in which these tissues respond to implant materials. The problem of bone loss around cementless implants was discussed as a specific example of a biologic effect resulting in both bone remodelling and endosteal erosion.

Biocompatible Materials↗
PubMed1991

Automated real-time data acquisition and analysis of cardiorespiratory function.

Microcomputer generation of an automated record without complexity or operator intervention is desirable in many circumstances. We developed a microcomputer system specifically designed for simplified automated collection of cardiorespiratory data in research and clinical environments. We tested the system during possible extreme clinical conditions by comparison with a patient simulator. Ranges used were heart rate of 35-182 beats per minute, systemic blood pressures of 65-147 mmHg and venous blood pressures of 14-37 mmHg, all with superimposed respiratory variation of 0-24 mmHg. We also tested multiple electrocardiographic dysrhythmias. The results showed that there were no clinically relevant differences in vascular pressures, heart rate, and other variables between computer processed and simulator values. Manually and computer recorded physiological variables were compared to simulator values and the results show that computer values were more accurate. The system was used routinely in 21 animal research experiments over a 4 month period employing a total of 270 collection periods. The file system integrity was tested and found to be satisfactory, even during power failures. Unlike other data collection systems this one (1) requires little or no operator intervention and training, (2) has been rigorously tested for accuracy using a wide variety of extreme patient conditions, (3) has had computer derived values measured against a standardized reference, (4) is reliable against external sources of computer failure, and (5) has screen and printout presentations with quick and easily understandable formats.

Computer Systems↗
PubMed1991

Mechanisms of cyclosporine A toxicity in defined cultures of renal tubule epithelia: a role for cysteine proteases.

The mechanisms of toxicity of cyclosporine A (CsA) were studied in primary cultures of individually microdissected rabbit and human renal tubules of proximal and distal regions of the nephron. A direct toxic effect of CsA on renal tubule epithelia was demonstrated using nigrosine uptake and LDH release as indicators of cell death. Proximal convoluted tubules (PCT) and proximal straight tubules (PST) were shown to be highly sensitive, while thick ascending limbs of Henle (TAL) were much less sensitive and cortical collecting tubules (CCT) relatively resistant. The effects of CsA were time and dose dependent over the range 50 ng/ml to 100 micrograms/ml. Protection against CsA-induced PST cell death was afforded by reduction in extracellular calcium levels in the media or addition of the calcium entry antagonists: verapamil, nifedipine or diltiazem. In addition, treatment with the cysteine protease inhibitor, E64, attenuated CsA-induced cell damage. A role for the lysosomal cysteine proteases (cathepsins), however, was ruled out on the basis of identical activity levels in all cell types; no beneficial effects of lysosomal enzyme depletion and no evidence of lysosomal rupture prior to death. By contrast, a role for the cytoplasmic, calcium-dependent cysteine protease calpain was suggested since activity levels were significantly higher in PST than CCT cultures and were inducible by CsA.

Animals↗
PubMed1991

Aberrant epithelial cell growth in autosomal dominant polycystic kidney disease.

Renal cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased epithelial cell proliferation and fluid accumulation. Using monolayer epithelial cultures derived from individually microdissected human ADPKD cysts and immunolocalization studies in vivo, the roles of matrix and growth factors in aberrant ADPKD cell proliferation have been studied. Abnormal ADPKD basement membrane ultrastructure was associated with increased turnover of 35S-labeled heparan sulfate proteoglycans (HSPG) by comparison to normal renal tubule epithelia in vitro. Mitogenic assays demonstrated significant increase in 3H-thymidine incorporation into ADPKD epithelia grown on type I and type IV collagen by comparison to normal proximal straight tubules (PST), collecting ducts, and thick ascending limbs of Henle (TAL). Proliferation on laminin or fibronectin matrices was unchanged and immunolocalization of matrix proteins was polarized and restricted to basal membranes of both ADPKD cysts and renal tubule epithelia in vivo. ADPKD epithelia in vitro were hypersensitive to the mitogenic action of epidermal growth factor (EGF) and EGF immunoreactivity was detected in ADPKD cyst lining epithelia, in cyst fluid, and in conditioned media from confluent ADPKD cultures, suggesting an autocrine mechanism of growth regulation. In addition, inhibition of epithelial proliferation by transforming growth factor-beta (TGF-beta), which was 100% in normal renal tubule epithelia, was reduced to 41% in ADPKD epithelia.

Cell Division↗
PubMed1991

Albumin escape from microvessels in kidney, heart and skeletal muscle in experimental diabetes mellitus in the anaesthetized rat.

Diabetes was induced with streptozotocin in rats weighing about 160 g. These were maintained with age-matched controls for up to 14 months, blood glucose being periodically monitored. Half the diabetic and control rats received the aldose reductase inhibitor, Ponalrestat, in their diet. Distribution of volumes of 131I-albumin (5 min) and 125I-albumin (100 min) were estimated in various tissues at 3 weeks, 6-7 months and 13-14 months of diabetes. The former space was assumed to represent the intravascular plasma space, while the latter was taken to include both the extravascular and intravascular albumin volumes in the kidney. In heart and skeletal muscle, equilibration between the specific activities of extravascular albumin and of plasma albumin was not assumed to be complete at 100 min. In the cortex and medulla of kidney, the extravascular albumin pool increased significantly at 13-14 months of diabetes (for both, P less than 0.01). Significantly increased entry of albumin into the interstitium occurred at 6 months (P less than 0.05) and at 13-14 months (P less than 0.01) in skeletal muscle, and at 13-14 months (P less than 0.05) in heart. The intravascular plasma volumes were not influenced by diabetes and the aldose reductase inhibitor had no effect at any time in either diabetic or control rats. These findings indicate increased movement of plasma albumin into the interstitium in the late phase of diabetes in the heart, skeletal muscle and in the kidney. Enlargement of the interstitial albumin pool is likely to affect the fluid balance between capillary and interstitium and may contribute to the effect of diabetes on the function of these organs.

Albumins↗
PubMed1991

Reversed polarity of Na(+) -K(+) -ATPase: mislocation to apical plasma membranes in polycystic kidney disease epithelia.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder in which renal tubules become enormously enlarged due to fluid accumulation. Na(+) -K(+) -ATPase was compared in normal and cystic regions of whole kidneys and in confluent primary cultures of microdissected renal tubule and cyst-lining epithelia. Immunostaining with antibodies directed against the Na(+) -K(+) -ATPase catalytic alpha-subunit was confined to apical, luminal plasma membranes of ADPKD epithelia, which was a complete reversal of the normal renal tubule polarized location in basolateral membranes. Mislocated Na(+) -K(+) -ATPase was shown to be functionally active, because identical intense apical staining was observed by use of a cytochemical assay. In addition, biochemical assays showed a significant increase in these ouabain-inhibitable Na(+) -K(+) -ATPase specific activity levels in ADPKD kidneys compared with age-matched normal kidneys. Specific binding of [3H] ouabain was not only increased but also confined to the apical membrane vesicles prepared from cystic regions of ADPKD kidneys compared with normal age-matched controls, in which binding was confined to basolateral membrane vesicles. Although steady-state levels of Na(+) -K(+) -ATPase alpha- and beta-subunit in mRNAs were increased somewhat in ADPKD kidneys, this alone was not sufficient to account for the observed activation. Confluent ADPKD epithelia grown on dual-chamber, permeable membrane supports also showed reversed polarity of 22NaCl vectorial transport, because this was from basal to apical media compartments. Because this transport could also be blocked by ouabain, this suggested apical Na(+) -K(+) -ATPase was responsible and implicated altered polarity of Na(+) -K(+) -ATPase and resultant Na+ secretion as a mechanism for cyst formation in ADPKD. Because no reversal of polarity of other basolateral or apical membrane proteins was detected, an intracellular sorting defect specific for Na(+) -K(+) -ATPase is proposed.

Biological Transport↗
PubMed1991

Dependencies of respiratory system resistance and elastance on amplitude and frequency in the normal range of breathing.

We calculated respiratory system resistance (Rrs) and elastance (Ers) from pressure and flow at the mouth in six seated subjects relaxed at FRC (cheeks tightly compressed) during sinusoidal volume forcing (250, 500, and 750 ml) at 0.2, 0.4, and 0.6 Hz. Dependencies of Rrs and Ers on frequency and tidal volume were generally the same in each subject; Rrs tended to decrease with frequency and tidal volume, whereas Ers tended to increase with frequency and decrease with tidal volume. Multiple linear regression of combined data indicated that the frequency and tidal volume effects on Rrs and Ers were significant (p less than 0.05), and that the effects on Rrs decreased at higher flows. Average Rrs was highest (4.43 cm H2O/L/s +/- 0.21 SE) at 0.2 Hz-250 ml, and lowest (3.07 cm H2O/L/s +/- 0.37) at 0.6 Hz-750 ml. Average Ers was highest (12.1 cm H2O/L +/- 1.1) at 0.6 Hz-250 ml, and lowest (7.1 cm H2O/L +/- 0.6) at 0.2 Hz-750 ml. We conclude that frequency and tidal volume dependencies in Rrs and Ers in the normal range of breathing should be considered when interpreting measurements of respiratory system impedance or developing models to describe the mechanical behavior of the respiratory system.

Airway Resistance↗
PubMed1991

Varus rotational femoral osteotomies in adults with hip dysplasia.

Fifty-six hips in 48 consecutive patients operated on for congenital dysplasia of the hip during the years 1971 through 1986 were evaluated for an average follow-up period of nine years (range, two-21 years). Twenty-three percent of the patients were treated with revision to total hip arthroplasty by the time of follow-up examination. The average time before revision was 8.6 years. All but three of the remaining hips were rated good or excellent (72%). These patients tended to have minimal or no preoperative degenerative joint disease. Complications included one subtrochanteric fracture, two cases of loss of fixation, and one superficial wound infection. The authors conclude that the operation provides predictable, high-quality results in those patients with minimal or no degenerative changes preoperatively. In those patients with mild or moderate degenerative changes, it may forestall the onset of severe symptoms by several years.

Adolescent↗